Diet and fatty acid pattern among patients with SLE: associations with disease activity,blood lipids and atherosclerosis

Abstract

Objective: As atherosclerosis is increased in systemic lupus erythematosus (SLE) we compared dietary habits in patients with SLE with controls, and in the patients studied associations of diet components, especially fatty acids (FAs), with disease activity, serum lipids and carotid plaque presence. Methods: In all 114 patients with SLE and 122 age- and sex-matched population-based controls answered a food frequency questionnaire (FFQ). Subcutaneous abdominal fat cell aspiration was analysed as to FA content and plaque occurrence was determined by B-mode ultrasound. Results: The total diet energy intake did not differ between patients and controls. However, the patients with SLE reported a higher intake of carbohydrate, lower fibre intake and lower intake of omega-3 and omega-6, than controls (p < 0.05). In the patients, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in adipose tissue (AT) correlated negatively with disease activity (SLEDAI), r = −0.36, p = <0.001 and r = −0.33, p = < 0.001, respectively. AT omega-3 was further positively associated with serum apoA1, r = 0.29, p = 0.004, whereas AT omega-6 showed a negative association, r = −0.21, p = 0.040. These FAs also had opposite associations with plaque presence, EPA and were DHA negative, r = −0.32, p = 0.002 and r = −0.33, p = 0.001, respectively, and omega-6 positive, r = 0.22, p = 0.027. The carbohydrate intake was positively correlated to AT omega-6, r = 0.38, p < 0.001, and negatively with serum apoA1, r = −0.27, p = 0.005. Conclusion: The macronutrient dietary pattern is different in SLE as compared with controls. The low intake of omega-3 and high intake of carbohydrate among patients with SLE appear to be associated with worse disease activity, adverse serum lipids and plaque presence.

Keywords

Systemic lupus erythematosus (SLE)cardiovascular disease diet fatty acids

Introduction

During recent years, the increased risk of cardiovascular disease (CVD) and atherosclerosis in systemic lupus erythematosus (SLE) have been much discussed. In SLE a combination of traditional and non-traditional risk factors contribute to the increased risk of CVD.¹ Traditional risk factors include hypertension, renal disease and dyslipidaemia, while the role of smoking varies between studies. Interestingly, accelerated atherosclerosis have been reported in SLE, more as increased prevalence of atherosclerotic plaques than as a generally increased intima-media thickness (IMT), which appears to be unchanged.^2,3

Relatively little is known about associations between rheumatic disease and diet. In rheumatoid arthritis (RA) a gluten-free vegan diet could improve the situation.^4,5 Also, Mediterranean diet has been reported to be beneficial.^6,7 Further, omega-3 fatty acids (FAs) are in general believed to be anti-inflammatory, and studies indicate that substitution with such compounds may ameliorate rheumatic disease.^8,9 On the other hand, omega-6 FAs have pro-inflammatory properties.¹⁰

In SLE the knowledge is still scarce about the impact of diet on the disease. The aims of the present study were therefore to investigate the dietary habits in relation to FAs in subcutaneous adipose tissue (AT), disease activity and atherosclerosis.

Patients and methods

Study group

Altogether, the 114 patients with SLE included in the SLEVIC (SLE vascular impact cohort) study¹¹ were recruited. They fulfilled the 1982 revised criteria of the American College of Rheumatology (ACR) for SLE¹² and were younger than 70 years. Of the 114 patients, 42 were treated with glucocorticoids at the time of the study. Further, the 122 age- and sex-matched controls (recruited randomly from the same catchment area), also recruited to the SLEVIC study, agreed to participate. The study was approved by the Karolinska Institutet research ethics committee and is in accordance with the Helsinki Declaration. All subjects gave informed consent before entering the study.

Assessments

The investigation included written questionnaires, an interview and physical examination by a rheumatologist, laboratory measurements, subcutaneous abdominal fat cell aspiration and ultrasound examination of the carotid arteries.

Disease activity and damage

SLE activity was determined by the Systemic Lupus Activity Measure (SLAM), which is a global score assessing overall disease activity occurring in the month preceding the assessment with a score ranging from 0 to 84,¹³ and also with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).¹⁴ SLEDAI includes the manifestations most commonly contributing to disease activity and are scored based on the presence or absence within 10 days of the evaluation.

Organ damage was determined with Systemic Lupus International Collaborating Clinics (SLICC) damage index.¹⁵ This index includes cumulative damage in 12 organ systems since the onset of SLE, with a score ranging from 0 to 47.

Dietary assessment

A self-administered, semi-quantitative food frequency questionnaire (FFQ) was used.¹⁶ In that the participants were asked to report their frequency of use of 88 food items and beverages over the past year. The nutrient calculations were carried out using nutrient composition values from the Swedish National Food Administration data.¹⁷ The intake of nutrients was computed by multiplying the frequency of consumption of each food item by the nutrient content of the specified portions. Dietary intake is described as the percentage of total intake. According to the Swedish National Food Administration the proportions (energy percentage, E%) of carbohydrate, protein and fat should be 55–65 E%, 10–15 E% and 25–35 E%, respectively, for normally active individuals. For less active individuals the recommendations are 55 E%, 16 E% and 28 E%, respectively.¹⁸

Assays

Venous blood samples were collected between 07:30 and 10:00 after an overnight fast. The biochemical variables were determined by standard laboratory methods. They included, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), blood lipids and lipoproteins.

Subcutaneous abdominal fat cells were aspirated with a needle attached to a vacuum tube and stored at −70 C until analysed for FAs. The FA composition of subcutaneous AT was analysed by gas liquid chromatography as described previously.¹⁹ The amounts of FAs were given as the relative percentage of the sum of the FAs analysed.

Carotid B-mode ultrasonography

The right and left carotid arteries were examined with a duplex scanner (Sequoia, Siemens Acuson, Mountain View, CA, USA) using a 6 MHz linear array transducer. The intima-media thickness (IMT) was defined as the distance between the leading edge of the lumen-intima echo and the leading edge of the media-adventitia echo in the far wall. The examinations were digitally stored for subsequent analyses by a computer system²⁰ with automated tracing of echo interfaces and measurements of distances between the wall echoes within a 10 mm long section of common carotid artery (CCA) in late diastole, defined by a simultaneous electrocardiographic recording. The mean values of the IMT within the 10 mm long section were calculated. When a plaque was observed in the region of the CCA measurements, the IMT was not measured.

Carotid plaque was defined as a localized IMT of >1 mm and at least a 100 per cent increase in thickness compared with adjacent wall segments. Plaque was screened for in the common, internal and external carotid arteries. Plaque occurrence was scored as the absence of plaque, the presence of unilateral plaque and the presence of bilateral plaque.

The differences between repeated measurements of IMT, by using the automated analysing system, were 4.9 per cent (coefficient of variation), with an IMT of 0.44–1.02 mm. The ultrasonographic methods used have been described in detail previously.^21,22

Statistics

The results were dichotomized or determined as continuous variables as indicated. We calculated percentiles based on distributions in the whole study group. Age, gender and geography were matched by the design of the study. Data are presented as means (with 95% confidence intervals, CI) or medians (with interquartile ranges, IQRs) depending on their distribution. Comparisons between groups were made with the Mann–Whitney U test, median test or Student’s t test. To evaluate the association between intake of FAs in the diet and their relative content in AT Spearman rank correlation analysis was used. Spearman rank correlation analysis was also used to evaluate the associations between measurements of the SLE disease and atherosclerosis. P-values <0.05 were considered significant. The statistical analysis program STATISTICA 9 (Stat Soft Scandinavia AB, Uppsala, Sweden) was used for statistical analysis.

Results

The characteristics of the patients with SLE and controls, which have been reported earlier,¹¹ are presented for background information in Table 1. There was no significant difference in smoking habits or frequency of diabetes. CRP and ESR were higher in the patients. According to SLAM and SLEDAI the patients had a fairly low disease activity and SLICC indicated only minor organ damage. Concerning the patients with SLE the characteristics as well as the adipose and serum lipids did not differ between those treated with glucocorticoids and those not, with the exception of a higher CRP in glucocorticoid-treated patients.

Table 1

Demographic and disease characteristics among SLE patients and controls¹¹

	Cases N = 114	Controls N = 122	p-value
Age	47.9 (45.5–50.4)	49.1 (46.8–51.4)	0.48
Female gender,% (N)	88 (100)	89 (109)	0.69
Smokers, % (N)	14 (16)	16 (19)	0.46
Diabetes, % (N)	5 (6)	2 (3)	0.22
SLE disease duration, years^a	9.0 (5.0–17.0)	–
SLAM	6.0 (4.0–9.0)	–
SLEDAI	2.0 (0–6.0)	–
SLICC	1.0 (0–3.0)	–
CRP, mg/L^a	1.90 (0.80–4.8)	1.0 (0.5–2.5)	<0.001
ESR, mm/h^a	21 (11–29)	8 (5–13)	<0.001
Plaque, % (N)	43 (49)	30 (37)	0.029
IMT, mm	0.62 (0.59–0.64)	0.63 (0.60–0.65)	0.43

Median.

Data are presented as mean (CI) for normally distributed variables and as median (inter-quartile range) for non-parametric variables.

N: number; SLAM: Systemic Lupus Activity Measure; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; SLICC: Systemic Lupus International Collaborating Clinics damage index.

Dietary intake and fatty acid profiles in adipose tissue

The mean dietary intake levels of total energy, carbohydrate, protein and fat are shown in Table 2.

Table 2

Dietary intake among the SLE cases and controls

	Cases all N = 114	Controls all N = 122	p-value
Total energy intake kcal/day	1940 (1799–2081)	1876 (1750–2001)	0.50
Fibres, E%	2.75 (2.56–2.94)	2.97 (2.80–3.13)	0.025
Carbohydrate, E%	49.8 (48.5–51.1)	47.3 (46.0–48.6)	0.007
Protein, E%	17.9 (17.4–18.5)	18.7 (18.1–19.2)	0.054
Total fat, E%	29.8 (28.6–31.0)	31.2 (30.2–32.2)	0.07
SFAs, E%	13.0 (12.2–13.7)	13.4 (12.7–14.1)	0.35
MUFAs, E%	10.1 (9.7–10.5)	10.5 (10.2–10.9)	0.11
PUFAs, E%	4.46 (4.25–4.67)	4.85 (4.60–5.09)	0.019
Omega-3, E%^a	0.88 (0.70–1.10)	0.93 (0.76–1.18)	0.049
Omega-6, E%^a	3.27 (2.78–3.81)	3.48 (2.95–4.20)	0.017

Median.

Data are presented as mean (confidence interval) for normally distributed variables and as median (inter-quartile range) for non-parametric variables.

E%: energy percentage; MUFAs: monounsaturated fatty acid; PUFAs: polyunsaturated fatty acids; SFAs: saturated fatty acids.

There were no significant differences in total energy intake between patients and controls and the total intake was comparable with the Swedish Food Recommendations.¹⁸ However, as to the diet composition the patients with SLE reported significantly higher intake of carbohydrate, with significant lower fibre intake, and significantly lower intake of poly-unsaturated fatty acids (PUFAs), that is, omega-3 and omega-6, than the controls.

The reported dietary intake, by both patients and controls, of the omega-3 essential FAs, eicosapentaenoic acid (EPA, 20:5 n3) and docosahexaenoic-acid (DHA, 22:6 n3) correlated significantly with that in AT, r = 0.35, p ≤ 0.001 and r = 0.40, p ≤ 0.001, respectively. The dietary linoleic acid (FA 18:2 n6) correlated significantly with that in AT (r = 0.18, p = 0.010). However, dietary arachidonic acid (FA 20:4 n6) did not correlate at all. This is probably a reflection of the role this FA has in the inflammatory process. These results verify the reliability of the long-term FA intake according to the FFQ.

The patients’ dietary intake of carbohydrates E% correlated significantly and positively with linoleic acid (18:2 n6) in AT (r = 0.38, p < 0.001). This was also verified when subdividing the intake into tertiles. Thus the patients with SLE who had the highest intake of carbohydrate, that is the third tertile, had significantly higher levels of 18:2 n6 in their AT, than those with the lowest intake, that is, the first tertile, of carbohydrate (p = 0.011).

Dietary intake and adipose fatty acids: associations with SLE disease

Dietary intake of carbohydrates E%, fibres E%, saturated fatty acids and total monounsaturated fatty acids did not significantly correlate with SLAM, SLEDAI or SLICC (data not shown). On the other hand dietary intake of the omega-6 fatty acid linoleic acid (18:2 n6) correlated positively with SLAM (r = 0.21, p = 0.028), but not with SLEDAI and SLICC.

Further, as shown in Table 3, AT EPA (20:5 n3) and DHA (22:6 n3) correlated negatively with SLEDAI, r = −0.36, p = <0.001 and r = −0.33, p = <0.001, respectively, and AT DHA negatively also with SLAM, r = −0.24, p = 0.021. No significant correlations were found between AT EPA and AT DHA and SLICC. However, the AT omega-6 metabolite arachidonic acid, 20:4 n6, correlated significantly and positively with SLICC, r = 0.20, p = 0.045.

Table 3

Spearman correlation coefficients between relative (percentage of total fat) FA content in adipose tissue and the SLE disease

	18:2 n6 AT	20:4 n6 AT	20:5 n3 AT	22:6 n3 AT
SLAM	0.04	0.03	−0.18	−0.24^c
SLEDAI	0.05	0.14	−0.36^a	−0.33^a
SLICC	0.06	0.20^c	0.15	0.16

p < 0.001, ^bp ≤ 0.01, ^cp ≤ 0.05.

18:2 n6: linoleic acid; 20:4 n6: arachidonic acid; 20:5 n3: eicosapentaenoic acid (EPA); 22:6 n3: docosahexaenoic acid (DHA); AT: adipose tissue; FA: fatty acids; SLAM: Systemic Lupus Activity Measure; SLEDAI: Systemic Lupus Erythematosus diseases activity index; SLICC: Systemic Lupus International Collaborating Clinics damage index.

Carbohydrate intake and AT fatty acids: associations with serum lipids among patients with SLE

Dietary intake of carbohydrate E%, correlated significantly and negatively with serum HDL (r = −0.28, p = 0.003) as well as with apoA1 (r = −0.27, p = 0.005) whereas fibre E% did not significantly correlate with these serum lipids. Concerning the FAs in AT, both DHA and EPA correlated positively with serum apoA1, r = 0.29, p = 0.004 and r = 0.22, p = 0.029, respectively. Linoleic acid (18:2 n6) correlated negatively with apoA1, r = −0.21, p = 0.037. No significant correlations were found between dietary intake of carbohydrate E%, omega-3 and omega-6 or AT omega-3 and omega-6 and triglycerides.

Occurrence of plaque

As reported earlier these patients with SLE had an increased occurrence of plaque in the carotid arteries compared with the controls, 42.98 per cent (n = 49) versus 30.32 per cent (n = 37), p = 0.029, whereas carotid intima measures (IMT) were similar.¹¹

Both patients and controls with plaque were older than those without (p < 0.001). The patients with plaque had a longer disease duration and were more damaged, according to SLICC (p = 0.038) than those without plaque. The total intake of glucocorticoid medications was not associated with atherosclerotic plaques.¹¹

Relationship between dietary intake, AT fatty acid profile, serum lipids and occurrence of plaque among the patients with SLE

When calculated on all patients, neither the dietary carbohydrate E%, fibre E%, omega-3 and omega-6 did significantly correlate with plaque occurrence (data not shown). As to AT omega-3 we found a significant negative correlation between omega-3 and plaque presence among the patients, whereas a positive correlation was found between omega-6 and plaque (Table 4).

Table 4

Spearman correlation coefficients between fatty acids in adipose tissue and plaque occurrence among patients with SLE (N = 114)

	Plaque
	r	p-value
Omega-3, %, AT	−0.20	0.049
Omega-6, %, AT	0.22	0.027
18:2 n6, %, AT	0.24	0.019
20:5 n3, %, AT	−0.32	0.002
22:6 n3, %, AT	−0.33	0.001

18:2 n6: linoleic acid; 20:5 n3: eicosapentaenoic acid (EPA); 22:6 n3: docosahexaenoic acid (DHA); AT: adipose tissue.

The significant positive correlation between dietary intake of carbohydrate E% and AT omega-6, mentioned above, differed in potency dependant on plaque presence or not. Thus, in patients with plaque the coefficient was r = 0.45, p < 0.001, whereas a weaker correlation was found among those without plaque (r = 0.29, p = 0.05).

Discussion

We report here that patients with SLE consume less PUFAs and fibres and more carbohydrates, as compared with age- and sex-matched healthy controls, and that the dietary intake of essential FAs was well reflected in AT FA content. An important finding was that among the patients the AT content of omega-3 was negatively associated with disease activity and plaque presence and positively with serum apoA1. The AT omega-6 FA was positively associated with SLE damage and plaque presence but negatively with serum apoA1. Furthermore, among the patients, the dietary intake of carbohydrates was not associated with disease activity or severity, but was positively correlated with AT omega-6 and negatively with serum HDL and apoA1.

The reliability of the long-term FA intake according to the FFQ was verified by the significant correlations found between the PUFAs ingested and those in AT in subcutaneous fat from the abdominal region. PUFAs in AT are largely exogenous and hence valid markers to assess dietary intake.^23,24

Lifestyle factors in SLE have not been much studied, and to the best of our knowledge, this is the first time dietary factors are studied in more detail in SLE. Even though it is recognized that in the general population diet may play a major role in disease, especially CVD, it has been difficult to demonstrate exactly how with the same certainty as in controlled double-blinded studies on medications. Recently, the role of different macro-nutrients in the diet as risk factors for atherosclerosis and CVD has been debated and re-evaluated. While diet recommendations typically include decreases in fat and especially saturated fat,²⁵ it has been difficult to demonstrate their efficacy in controlled studies. In the largest intervention study, Women’s Health Initiative (WHI), reduced total fat intake and increased intakes of vegetables, fruits and grains did not significantly reduce the risk of CVD in postmenopausal women and achieved only modest effects on CVD risk factors including blood lipids.²⁶

Among the present patients with SLE the intake of PUFAs was significantly decreased compared with controls, while there were no differences in monounsaturated and saturated fat. Studies on SLE and intake of omega-3 are scarce but in a study from 2004, supplementation with omega-3 fish oils was found to reduce symptomatic disease activity.²⁷ Such a benefit of omega-3 is supported by the present finding that AT omega-3 was negatively associated with disease activity.

The impact of dietary omega-3, especially EPA (20:5n-3) and DHA (22:6 n-3) on rheumatoid inflammation has been investigated in many studies. Several randomized controlled studies have shown that supplementation with fish oil in addition to ordinary pharmacological treatment results in beneficial effects on RA symptoms, such as decreased number of tender and swollen joints as well as an NSAID-sparing effect.^8,9

With regard to inflammation it is often considered that it is the PUFAs omega-3 and omega-6 that are most important, these often acting to oppose one another’s actions, which could explain the opposite correlations found here for AT omega-3 and omega-6 with disease activity and plaque occurrence. Cells involved in the inflammatory response are typically rich in the omega-6 FA, arachidonic acid (a metabolite of linoleic acid) which is a precursor to inflammatory eicosanoids.²⁸ Eicosanoids produced from arachidonic acid include various prostaglandins, thromboxanes and leucotrienes. These have well-established roles in regulation of inflammation, immunity and platelet aggregation.²⁹ It is possible that these mechanisms have an impact on the development of atherosclerosis. Interesting to note is that there are data suggesting that atherosclerotic plaques can incorporate the omega-3 FA EPA, and that a higher content of EPA in carotid plaques is associated with a reduced number of foam cells and T cells, less inflammation and increased stability.³⁰ Further, AT content of EPA and DHA, has been shown to be significantly lower in subjects suffering a primary non-fatal MI than in healthy controls.³¹

The above mentioned reports on the beneficial effect of omega-3 FAs are supported by the present findings that AT omega-3 were positively associated with serum apoA1 and negatively with plaque presence. Convincing evidence from extensive research over the past three decades points out the potential beneficial effects of omega-3 in primary prevention, CHD, post-MI and atherosclerosis.³²

Another finding in the present study is that intake of fibre was lower and intake of carbohydrates higher, among patients with SLE as compared with the controls. The role of fibre intake in human disease is less debated than other macro nutrients, and many studies indicate that fibre intake is negatively associated with human disease.³³ Recommendations regarding carbohydrates depend on factors including glycaemic index (GI) and there is thus a consensus that fast carbohydrates are negative. A caveat in the present study is that the design does not allow for detailed analysis of type of carbohydrates involved. It is, however, interesting to note that low carbohydrate intake was associated with high HDL and apoA1, while high carbohydrate intake had opposite associations. This could be a reflection of the low fibre content in the diet. HDL may be an important factor in SLE, due to its anti-inflammatory and anti-atherogenic properties.^1,2,34,35

Interestingly, carbohydrate intake has recently been implicated as a risk factor for CVD, especially refined carbohydrates which promote a swift increase in blood glucose, with ensuing insulin increases.³⁶ In line with this, diabetics in the WHI study experienced an adverse glycaemic effect of the low-fat diet³⁷ and an opinion appearing to be on the rise is that dietary efforts to improve the CVD risk should emphasize limitation of refined carbohydrate intake and a reduction in excess adiposity.³⁶

The limitations of the current study should be acknowledged. The cross-sectional design of our study limits the ability to ascribe causal relationships to the associations detected. Cross-sectional studies only provide a ‘snapshot’ of the outcome and the characteristics associated with it at a specific point in time.

Taken together, our findings indicate that the dietary patterns among the patients with SLE are different from a population-based control group, with lower intake of PUFAs, decreased intake of fibres and increased intake of carbohydrates. This diet may in different ways, directly or indirectly, contribute to increased inflammatory activity, disease damage, unfavourable lipid profile in serum and atherosclerosis.

Footnotes

Acknowledgements

We are grateful to the registered nurses Margareta Wörnert, Mona Westvall and Eva Waldheim for collecting clinical data and administration of patients and to Niclas Håkansson for statistical help.

Author contributions

J Frostegård and AC Elkan had the main responsibility for drafting the article, all authors were involved in revising it critically for important intellectual content, and all authors approved the final version to be published. J Frostegård and AC Elkan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. J Frostegård, C Anania, T Gustafsson and T Jogestrand

Acquisition of data. J Frostegård, C Anania, T Gustafsson and T Jogestrand

Analysis and interpretation of data. N Håkansson, I Hafström and J Frostegård together with AC Elkan who had the main responsibility for data analysis.

Funding

This study was supported by the Swedish Research Council, The regional agreement on medical training and clinical research (ALF) between Stockholm county council and the Karolinska Institutet, the King Gustav V 80 years foundation, The Swedish Rheumatism Association, CIDaT, Vinnova and the 6^th Framework Program of the European Union, Priority 1: Life sciences, genomics and biotechnology for health (grant LSHM-CT-2006-037227 CVDIMMUNE) with JF as coordinator.

Conflict of interest

The authors have no conflicts of interest to declare.

References

Svenungsson

Jensen-Urstad

Heimburger

. Risk factors for cardiovascular disease in systemic lupus erythematosus. Circulation 2001; 104: 1887–1893.

Frostegard

. Atherosclerosis in patients with autoimmune disorders. Arterioscler Thromb Vasc Biol 2005; 25: 1776–1785.

Roman

Shanker

Davis

. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003; 349: 2399–2406.

Elkan

Sjoberg

Kolsrud

. Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: a randomized study. Arthritis Res Ther 2008; 10: R34–R34.

Hafstrom

Ringertz

Spangberg

. A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatology (Oxford) 2001; 40: 1175–1179.

Skoldstam

Hagfors

Johansson

. An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann Rheum Dis 2003; 62: 208–214.

McKellar

Morrison

McEntegart

. A pilot study of a Mediterranean-type diet intervention in female patients with rheumatoid arthritis living in areas of social deprivation in Glasgow. Ann Rheum Dis 2007; 66: 1239–1243.

Galarraga

Youssef

. Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis. Rheumatology (Oxford) 2008; 47: 665–669.

Goldberg

Katz

. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 2007; 129: 210–223.

10.

Galli

Calder

. Effects of fat and fatty acid intake on inflammatory and immune responses: a critical review. Ann Nutr Metab 2009; 55: 123–139.

11.

Anania

Gustafsson

Hua

. Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus. Arthritis Res Ther 2010; 12: R214–R214.

12.

Hochberg

. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725–1725.

13.

Liang

Socher

Larson

. Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 1989; 32: 1107–1118.

14.

Petri

Hellmann

Hochberg

. Validity and reliability of lupus activity measures in the routine clinic setting. J Rheumatol 1992; 19: 53–59.

15.

Stoll

Seifert

Isenberg

. SLICC/ACR Damage Index is valid, and renal and pulmonary organ scores are predictors of severe outcome in patients with systemic lupus erythematosus. Br J Rheumatol 1996; 35: 248–254.

16.

Messerer

Johansson

Wolk

. The validity of questionnaire-based micronutrient intake estimates is increased by including dietary supplement use in Swedish men. J Nutr 2004; 134: 1800–1805.

17.

Bergström L, Becker EH, Hagman U. Vad är det vi äter? Livsmedelstabeller och livsmedelsdatabaser ger klart besked. Vår föda 2. In: Administration SNF, editor. 1997.

18.

Administration NF. Swedish Nutrition Recommendations Objectified (SNO), 2005, www.slv.se. National Food Administration, 2005.

19.

Boberg

Croon

Gustafsson

Vessby

. Platelet fatty acid composition in relation to fatty acid composition in plasma and to serum lipoprotein lipids in healthy subjects with special reference to the linoleic acid pathway. Clin Sci (Lond) 1985; 68: 581–587.

20.

Wendelhag

Liang

Gustavsson

Wikstrand

. A new automated computerized analyzing system simplifies readings and reduces the variability in ultrasound measurement of intima-media thickness. Stroke 1997; 28: 2195–2200.

21.

Lemne

Jogestrand

de Faire

. Carotid intima-media thickness and plaque in borderline hypertension. Stroke 1995; 26: 34–39.

22.

Nowak

Nilsson

Sylven

Jogestrand

. Potential of carotid ultrasonography in the diagnosis of coronary artery disease: a comparison with exercise test and variance ECG. Stroke 1998; 29: 439–446.

23.

Baylin

Kabagambe

Siles

Campos

. Adipose tissue biomarkers of fatty acid intake. Am J Clin Nutr 2002; 76: 750–757.

24.

Wolk

Vessby

Ljung

Barrefors

. Evaluation of a biological marker of dairy fat intake. Am J Clin Nutr 1998; 68: 291–295.

25.

Astrup

Dyerberg

Elwood

. The role of reducing intakes of saturated fat in the prevention of cardiovascular disease: where does the evidence stand in 2010? Am J Clin Nutr 2011; 93: 684–688.

26.

Howard

Van Horn

Hsia

. Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295: 655–666.

27.

Duffy

Meenagh

McMillan

. The clinical effect of dietary supplementation with omega-3 fish oils and/or copper in systemic lupus erythematosus. J Rheumatol 2004; 31: 1551–1556.

28.

Calder

. Long-chain fatty acids and inflammation. Proc Nutr Soc 2012; 28: 1–6.

29.

Calder

. Mechanisms of action of (n-3) fatty acids. J Nutr 2012; 142: 592S–599S.

30.

Cawood

Ding

Napper

. Eicosapentaenoic acid (EPA) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque EPA is associated with decreased plaque inflammation and increased stability. Atherosclerosis 2010; 212: 252–259.

31.

Pedersen

Ringstad

Almendingen

. Adipose tissue fatty acids and risk of myocardial infarction–a case-control study. Eur J Clin Nutr 2000; 54: 618–625.

32.

Lavie

Milani

Mehra

Ventura

. Omega-3 polyunsaturated fatty acids and cardiovascular diseases. J Am Coll Cardiol 2009; 54: 585–594.

33.

Park

Subar

Hollenbeck

Schatzkin

. Dietary fiber intake and mortality in the NIH-AARP diet and health study. Arch Intern Med 2011; 171: 1061–1068.

34.

Borba

Bonfa

. Dyslipoproteinemias in systemic lupus erythematosus: influence of disease, activity, and anticardiolipin antibodies. Lupus 1997; 6: 533–539.

35.

Svenungsson

Gunnarsson

Fei

. Elevated triglycerides and low levels of high-density lipoprotein as markers of disease activity in association with up-regulation of the tumor necrosis factor alpha/tumor necrosis factor receptor system in systemic lupus erythematosus. Arthritis Rheum 2003; 48: 2533–2540.

36.

Siri-Tarino

Sun

Krauss

. Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr 2010; 91: 502–509.

37.

Shikany JM, Margolis KL, Pettinger M, et al. Effects of a low-fat dietary intervention on glucose, insulin, and insulin resistance in the Women's Health Initiative (WHI) Dietary Modification trial. Am J Clin Nutr 2011; 94: 75–85.